DESCRIPTION (Applicant's Description) The average adult produces and in parallel eradicates 50-70 billion cells daily as a result of programmed cell death (apoptosis). Defects in apoptosis contribute to many human diseases, including cancer, where excessive cell accumulation due to failed programmed cell death is a common occurrence. Suppression of apoptosis contributes to carcinogenesis by several mechanisms, including prolonging cell life-span, thereby facilitating the accumulation of gene mutations; permitting growth factor-independent cell survival; promoting resistance to immune-based cytotoxicity; allowing disobeyance of cell cycle checkpoints which would normally induce apoptosis; and producing resistance to chemotherapy and radiation. This program project grant application addresses the mechanisms by which signal transduction pathways impinge on and regulate the core cellular machinery responsible for controlling apoptosis. The project brings together the talents of 6 co-investigators, who have strong track records of productivity and contribution to the field of apoptosis. Five projects and 2 cores are proposed, integrated around a central theme of understanding mechanisms of cell death regulation and dysregulation in normal and malignant cells. Among the questions under interrogation are: (1) Studies of the mechanisms by which TNF-family receptors generate signals that either inhibit or promote apoptosis, focusing on the involvement of TRAF-family proteins (Reed; Ware); (2) Investigations of the involvement of Death Domain-containing TNF-family receptors in the phenomenon of anoikis, i.e. apoptosis resulting from cell detachment (Frisch) - a biological process of great importance for tumor invasion, metastasis, and angiogenesis; (3) Analysis of the DCC (Deleted in Colon Cancer) gene product, an integral membrane receptor involved in cell adhesion which links to caspase-pathways controlling cell life and death (Salvesen; Bredesen); and (4) Elucidation of the role of mitochondria in deciding cell death commitment and the mechanisms that circumvent this caspase-independent cell suicide process in cancers (Green). Together, the cross-fertilization of ideas that emerges from these related projects will provide mechanistic insights into normal and aberrant apoptosis regulation, laying a foundation for future advances in the treatment of cancer and other diseases.